Discovery of 1 H- Pyrazole Biaryl Sulfonamides as Novel G2019S-LRRK2 Kinase Inhibitors

Robert K Leśniak; R Jeremy Nichols; Marcus Schonemann; Jing Zhao; Chandresh R Gajera; Grace Lam; Khanh C Nguyen; J William Langston; Mark Smith; Thomas J Montine

doi:10.1021/acsmedchemlett.2c00116

Discovery of 1 H- Pyrazole Biaryl Sulfonamides as Novel G2019S-LRRK2 Kinase Inhibitors

ACS Med Chem Lett. 2022 May 23;13(6):981-988. doi: 10.1021/acsmedchemlett.2c00116. eCollection 2022 Jun 9.

Authors

Affiliations

¹ Medicinal Chemistry Knowledge Center, Sarafan ChEM-H, Stanford University, Stanford, California 94305, United States.
² Department of Pathology, Stanford University, 300 Pasteur Drive, Stanford, California 94305, United States.
³ Departments of Medicine and Microbiology and Immunology, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California 94305, United States.
⁴ Department of Neurology and Neuroscience, Stanford University, 300 Pasteur Drive, Stanford, California 94304, United States.

Abstract

G2019S (GS) is the most prevalent mutation in the leucine rich repeat protein kinase 2 gene (LRRK2), a genetic predisposition that is common for Parkinson's disease, as well as for some forms of cancer, and is a shared risk allele for Crohn's disease. GS-LRRK2 has a hyperactive kinase, and although numerous drug discovery programs have targeted LRRK2 kinase, few have reached clinical development. We report the discovery and preliminary development of an entirely novel structural class of potent and selective GS-LRRK2 kinase inhibitors: biaryl-1H-pyrazoles.